1. Field of the Invention
The present invention relates generally to a novel use of Troglitazone and related thiazolidinedione derivatives. More specifically, it relates to the use of Troglitazone and related thiazolidinedione derivatives in the treatment of the climacteric. It also relates to the use of Troglitazone and the like for the treatment of cancer.
2. Description of Related Art
Troglitazone is a member of a class of antidiabetic drugs termed thiazolidinediones. Although the mechanism is unknown, this class of drugs lowers insulin resistance and improves glucose tolerance(Nolan el al., 1994). For these reasons Troglitazone has found use in the treatment of noninsulin-dependent diabetes mellitus (NIDDM) (U.S. Pat. No. 5,478,852 incorporated by reference herein). NIDDM, otherwise referred to as Type 11 diabetes, is the form of diabetes mellitus which occurs predominately in adults in whom adequate production of insulin is available for use, yet a defect exists in insulin-mediated utilization and metabolism of glucose in peripheral tissues. The population with impaired glucose tolerance progresses to NIDDM at a rate of 5% to 10% of cases per year. Failure to treat NIDDM can result in mortality due to cardiovascular disease and other diabetic complications including retinopathy, nephropathy, and peripheral neuropathy. Administration of Troglitazone can provide effective treatment of populations experiencing impaired glucose tolerance and may result in the delay or prevention of the onset of NIDDM.
Moreover, Troglitazone has been further implicated in the treatment of polycystic ovary syndrome (PCO). This is a syndrome in women that is characterized by chronic anovulation and hyperandrogenism. Women with this syndrome often have insulin resistance and an increased risk for the development of noninsulin-dependent diabetes mellitus. In women with PCO given Troglitazone (400 mg every day), insulin resistance was reduced and 2 of the 25 women studied had ovulatory menses (Dunaif et al., 1996).
While advances continue to be made in chemotherapy treatment of cancer, effective agents are still lacking for the treatment many types of cancer. One such type is mesenchymal tumors. The mesenchyma consists of the meshwork of embryogenic connective tissue in the mesoderm from which are formed the connective tissues of the body as well as blood vessels and lymphatic vessels. There are many types of mesenchymal tumors including but not limited to sarcomas (general), rhabdomyosarcomas, fibrosarcomas, retinoblastoma, hemangiopericytoma, congenital mesoblastic nephroma, and mesotheliomas (Pierce and Figlin, 1992; Odell, 1996; Connelly and Budd, 1996). These types of tumors are aggressive and fast growing, thus development of effective chemotherapeutic agents for their treatment is of particular need.
One mechanism through which thiazolidinediones are believed to have biological effect is their ability to serve as a high affinity ligand for the orphan steroid receptor peroxisome proliferator-activated receptor gamma (PPAR.gamma.) (Lehmann et al., 1995). PPARy is a member of the nuclear receptor superfamily of orphan steroid receptors that serve as transcription factors (Motojima, 1993). This family includes receptors for the steroid, thyroid and retinoid hormones. Activation of PPAR.gamma. is implicated in adipocyte differentiation through the activation of adipocyte-specific gene expression (Lehmann et al., 1995). This gene expression is mediated through binding to a PPAR.gamma. response element (PPRE) in the promoter region of target genes (Forman et al., 1995). This PPRE is composed of a directly repeating core site separated by one nucleotide (NNN-AGGTCA-N-AGGTCA) (SEQ ID NO:1). To bind to a PPRE, PPAR.gamma. must form a heterodimer with the 9-cis retinoic acid receptor (RXR). This sequence is classified as a DR-1 consensus sequence that is universal for orphan receptors (Vidal-Puig, 1996). Because of the universal nature of this consensus sequence, other transcription factors can bind to the PPRE and compete with the binding of PPAR.gamma.. One such transcription factor is COUP-TFII that antagonizes PPAR signaling in mammalian cells (Marcus et al., 1996).
PPAR.gamma. is in a family of three orphan receptors that are encoded by different genes (Motojima, 1993). The three PPAR genes are PPAR.alpha., PPAR.delta., and PPAR.gamma. (Motojima, 1993). Moreover, 2 isoforms of PPAR.gamma. also exist, PPAR.gamma.1 and .gamma.2 (Vidal-Puig et al., 1996). These 2 proteins differ only in their NH.sub.2 -terminal-30 amino acids and are the result of alternative promoter usage and differential mRNA splicing (Vidal-Puig et al., 1996). In addition to thiazolidinediones, another ligand for the PPAR.gamma. nuclear receptor is the arachidonic acid metabolite 15-deoxy-delta.sup.12, 14 -prostaglandin J.sub.2 (15d-PGJ.sub.2). This prostaglandin activates PPAR.gamma.-dependent adipogenesis, but activated PPAR.alpha. only at high concentrations (Forman et al., 1995; Kliewer et al., 1995). This is further evidence that the PPAR family subtypes are distinct from one another in their pharmacological response to ligands.
The climacteric is defined as the syndrome of endocrine, somatic and psychological changes occurring at the termination of the reproductive period in the female. The menstrual irregularities are episodes of prolonged menstrual bleeding caused by a loss of ovulation. The loss of ovulation is caused by a failure of development of ovarian follicles. Currently the most common method for treatment of the climacteric is hormone replacement, including administration of birth control pills, oral administration of estrogen and progesterone preparations or oral administration of progesterone only preparations (Shaaban, 1996). While relieving symptoms of the climacteric, these treatments have many associated risks and side effects. Risks associated with hormone treatment include endometrial carcinoma, hypertension, hyperlipidemia, cholelithiasis (gallstones), breast cancer, and deep venous thrombosis (Barentsen, 1996).
Compounds useful for practicing the present invention, and methods of making these compounds are known. Some of these compounds are disclosed in WO 91/07107; WO 92/02520; WO 94/01433; WO 89/08651; JP Kokai 69383/92; U.S. Pat. Nos. 4,287,200; 4,340,605; 4,438,141; 4,444,779; 4,461,902; 4,572,912; 4,687,777; 4,703,052; 4,725,610; 4,873,255; 4,897,393; 4,897,405; 4,918,091; 4,948,900; 5,002,953; 5,061,717; 5,120,754; 5,132,317; 5,194,443; 5,223,522; 5,232,925; and 5,260,445. The disclosure of these publications are incorporated herein by reference in particular with respect to the active compounds disclosed therein, and methods of preparation thereof.